Macitentan, N-[5-(4-Bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl]-N′-propylsulfamide, of formula I
is an endothelin receptor antagonist. It is mentioned on page 134 in WO 02/53557 A1 and can be prepared by slight modification of the method described for example 104.
Macitentan is a pharmaceutically active agent which can be used for the treatment of pulmonary arterial hypertension and being tested in clinical trials for that treatment.
The preparation of closely related compounds is described in WO 02/53557 A1. In particular, example 104 describes preparation of N-[5-(4-Bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl]-N′-ethylsulfamide as a precipitate.
WO 2007/031933 A2 describes pharmaceutical compositions comprising Macitentan. Macitentan as obtained from WO 02/53557 is used as the starting material for the production of pharmaceutical compositions (see WO 2007/031933 A2, page 1). Preferred compositions are prepared by blending Macitentan with intra-granular materials in a high shear mixer, granulating, drying, milling, blending the milled granule with extra-granular materials except lubricant, adding lubricant and blending again, and compressing the obtained mixture into tablets. WO 2007/031933 A2 states that by using the described starting materials and the described process for manufacture, stable formulations can be produced.
In a Note regarding amendments of European patent application No. 06809280.8 of Feb. 19, 2009, it is disclosed that the preparation of stable Macitentan-containing formulations is challenging because if certain components were missing or to be replaced by others that one skilled in the art would think are equivalent, the pharmaceutical composition would have altered properties that would make it less stable and/or unsuitable for certain types of formulations (page 3 of Note). Experiments are presented which are said to show that only particular combinations of excipients are suitable for the preparation of storage stable (chemical stability was tested) pharmaceutical compositions with satisfactory dissolution properties.
Bolli et al., J. Med. Chem. 2012, 55, 7849-7861 describe synthesis of Macitentan and proceed to prepare crystalline Macitentan free base by crystallization from methanol. This is the first disclosure of crystalline Macitentan free base, and crystalline Macitentan free base is described to have a melting point of 135° C.-136° C.
The pharmaceutical compositions described in the prior art have drawbacks in that only particular excipients can be used for the preparation of storage stable pharmaceutical compositions with still satisfactory dissolution properties. Moreover, the pharmaceutical compositions described in the prior art are not yet ideal with regard to storage stability and/or dissolution properties.